Project Summary/Abstract Caffeine is routinely used in the treatment of preterm (PT) infants with immature breathing patterns. We have documented persisting intermittent decreases in blood oxygen levels (intermittent hypoxia, IH) after stopping routine caffeine treatment about 6 weeks before the due date (34-35 weeks postmenstrual age, PMA). IH is pro-inflammatory and is associated with adverse effects on cognition and brain structure in patients with sleep apnea syndrome and in rodent models of apnea of prematurity. We address 2 significant questions in infants born at ? 30 wks gestation: 1) does IH occurring after stopping routine caffeine at 34-35 wks and persisting to 42 wks PMA cause injury, and 2) can this injury be attenuated by extending caffeine treatment to 42 wks PMA? Innovations include high resolution continuous pulse oximeter recordings to 43 wks PMA to quantify IH, measurement of inflammatory biomarkers, and quantitative magnetic resonance imaging (MRI) and MR spectroscopy (MRS) to assess structural and functional brain injury. Our prior studies confirm that IH occurs frequently after cessation of routine caffeine, and that extended caffeine treatment at age-appropriate dosing attenuates the extent of IH. Our hypotheses are that, compared to placebo, 1) caffeine-treated infants will have lower overall IH exposure between 34-34 and 42 weeks PMA, 2) the caffeine group will have less biomarker evidence of continuing inflammation, and these effects will be mediated by reduced IH exposure, 3) the caffeine group will have less structural, microstructural and metabolic biomarkers of acute brain injury as determined by MRI and MRS, and these effects will be mediated by reduced IH exposure in the extended caffeine group. We will enroll 220 PT infants. Eligible subjects will be enrolled as early as 32 wks PMA, when no longer having overt symptoms related to immature breathing pattern. Enrolled, infants will begin continuous pulse oximeter recordings of oxygen (O2) saturation. We will randomize 110 infants to caffeine at 10 mg/kg body weight twice daily and 110 to equal volume placebo starting the day after last dose of routine caffeine treatment, typically by 34-35 weeks PMA. Study drug will be continued until 42 weeks PMA, and pulse oximeter recordings will continue to 43 wks PMA. Two caffeine levels will be obtained, the 1st before discharge home and the 2nd at home. At study enrollment and completion at 43-45 wks PMA, inflammatory biomarkers and brain MRI/MRS will be obtained. Data collection will also include demographics, postnatal medical history, and medical status at hospital discharge and study completion. Our results will provide the justification for subsequent studies to assess longer term neurodevelopmental outcomes associated with persisting IH during a critical period of continuing brain maturation, and the attenuating effects of extended caffeine treatment. The knowledge gained will establish highly relevant and easily translatable new cost-effective strategies to significantly improve clinical practice and public health in infants born preterm at ? 30 wks gestation.